Study Describes Onset of Broadly Neutralizing Antibody Responses in HIV-infected Individuals
By Andreas von Bubnoff
Broadly neutralizing antibody (bNAb) responses in HIV-infected people become detectable on average two and a half years after infection, and in some cases as early as one year after infection, according to a study led by Leo Stamatatos, director of the viral vaccine program at Seattle BioMed, a non-profit research institute (PLoS Pathog. 7, e1001251, 2011). The study is the first to show the onset of bNAb responses in such detail, Stamatatos says.
The study also for the first time shows that HIV-infected individuals who developed bNAb responses had more CD4+ T cells expressing the Programmed Death 1 marker, potentially suggesting that these people have more follicular CD4+ T helper (TFH) cells in blood than people without such responses. These cells are believed to be important for affinity maturation of antibodies, which is thought to be important for the development of a bNAb response (see Vaccines to Antibodies: Grow Up!, IAVI Report, July-Aug. 2010).
The serum samples used in the study came from a Vanderbilt University cohort of 21 people and a cohort of 17 people from Massachusetts General Hospital in Boston, all infected with HIV clade B. The samples were isolated at several time points, from just months to almost seven years after infection. To qualify as broadly neutralizing, 20-fold or higher dilutions of the sera had to neutralize at least 75% of a panel of HIV isolates from clades A, B, and C. Based on this criterion, about a third (five of 17) of the individuals in the Boston cohort developed a bNAb response on average two and a half years after infection, Stamatatos says. A similar fraction of people with bNAb responses has also been observed in previous studies, he adds.
Sera from a few individuals in both cohorts neutralized around 50% of the HIV isolates at about one year after infection. Data from a few individuals that were followed for up to seven years suggested that if bNAb responses had not developed by about three and a half years, they did not develop later.
“The finding that cross-reactive neutralizing activity can develop so early after infection is new,” says Hanneke Schuitemaker, a professor of virology at the Academic Medical Center in Amsterdam, who was not involved in the study. In agreement with the new study, her group has previously reported that bNAb responses broaden over time (AIDS 23, 2405, 2009).
Stamatatos and colleagues also found that the specificity of the early responses around two and a half years after infection is directed to only a few targets on HIV Env, primarily the CD4binding site and targets on the native Env spike that are similar to the target of the bNAbs PG9 and PG16, which were isolated in 2009 by researchers at IAVI and The Scripps Research Institute (TSRI; see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct. 2009).
These targets are similar to some of the targets Laura Walker, a graduate student in Dennis Burton’s lab at TSRI, and colleagues identified in a recent study of the bNAb responses of 19 individuals, whose sera had among the broadest and most potent neutralizing activity from a cohort of 1,800 individuals infected for at least three years (see Antibody Fever, IAVI Report, Mar.-Apr. 2010; PLoS Pathog. 6, e1001028, 2010). The fact that the bNAb responses in both studies are directed to just a few similar epitope targets suggests that the specificity of the earliest and chronic bNAb responses is similar, and that these epitopes are very immunogenic in the context of HIV infection, says Stamatatos.
Walker says this similarity in the epitope targets is interesting, but points to several differences between the two studies that might make them hard to compare. For one, the new study only included people infected with HIV clade B and not clade C, whereas her study looked at individuals from Africa, many of whom were infected with HIV clade C. In addition, she says, the two studies used different virus panels to test the neutralization breadth of the sera.
Walker adds that her study used a more stringent definition of neutralization breadth than the new study by Stamatatos and colleagues—her study used at least 100-fold serum dilutions. “We are more interested in the best donors [and in] the epitopes targeted by the antibodies in those donors,” Walker says. “It may turn out that less broad neutralizing sera have different specificities than sera from elite neutralizers.”
But Noah Sather, a staff scientist in Stamatatos’ lab and a coauthor of the new study, says the intent of the two studies is different. He says while Walker and colleagues determined which epitopes are used by the top 5% of neutralizers selected from a very large cohort of HIV-infected individuals, Stamatatos and colleagues analyzed all HIV-infected individuals in their cohorts to determine when breadth begins to develop in the general population of HIV-infected individuals.